David Askenazi MD MSPH pCRRT meeting September 28, 2012 CRRT for Neonates David Askenazi MD MSPH pCRRT meeting September 28, 2012

Transparency…. I am on the speaker’s bureau for Gambro Will not be discussing specific differences of CRRT machines I will be talking about non-FDA indications for Devices No CRRT devices are approved for < 20 kg.

Educational Objectives Acute kidney injury and CRRT epidemiology Indications for RRT in children Type of RRT – PD vs. HD vs. CRRT Prescription of CRRT for pediatric patients Vascular access Priming the machine Anticoagulation Blood flow rates Clearance Net ultrafiltration goals

Children are not small adults Different Sizes, and Shapes 0 days to 21+ years 1.3 kg to 200 kg Not present Diabetes Older age Atherosclerotic disease Hypertension Volume of patients Present Size/Access variation Less frequent than adults/less experience Machinery is adapted (not made) for pediatrics

Small Children are not Big Children Blood Primes Access Machines are Really not designed for small children Need high blood flow /kg Need high clearances for citrate clearance Thermic Control is critical Not FDA approved for small children

“Just pull off the sticker” “Explain it to the family”

Indications for RRT in the ICU A -- Alkalosis or Acidosis ( metabolic) E -- Electrolyte disturbances -- Hyperkalemia -- hypocalcemia -- Hypernatremia -- hypercalcemia -- Hyperphosphatemia -- hyperuricemia I -- Intoxication with a drug that can be dialyzed I – Inborn Error of Metabolism O -- Overload of Fluids ( H20 retention) -- Pulmonary edema or hypertension U -- Uremia - Not azotemia which can be secondary to steroids, bleeding -- CNS encephalopathy, vomiting, pericarditis NOT AMNEABLE TO MEDICAL THERAPY

Neonatal AKI Definition Stage Serum Creatinine Criteria UOP criteria 1 ↑ SCr of ≥0.3 mg/dl or ↑ SCr to 150-199% of baseline UOP > 0.5 cc/kg/hr and ≤ 1 cc/kg/hr 2 ↑ SCr to 200%-299% x baseline UOP > 0.1 cc/kg/hr and ≤ 0.5 cc/kg/hr 3 ↑ SCr to ≥ 300% of baseline or SCr ≥ 2.5 mg/dl or Receipt of dialysis UOP ≤ 0.1 cc/kg/hr Baseline SCr will be defined as the lowest previous SCr value No Major Congenital Anomalies of the Kidney and Urinary Tract

Challenges to SCr Based Definitions SCr is a surrogate of FUNCTION not INJURY 25-50% functional loss is needed to for SCr changes to occur SCr is affected by medications, billirubin and muscle mass SCr rises in Pre-Renal Azotemia – Is that AKI?

Challenges to SCr based definitions in neonates Normal Creatinine levels x gestational age Gallini F: Pediatric Nephrology 2000 (15); 119-124

Epidemiology Neonatal AKI and CRRT

Neonatal AKI Premature Neonate Cardiopulmonary Bypass ECMO Cardiopulmonary Bypass Premature Neonate Infant with Peri-natal Asphyxia Sick Infant in NICU What are the outcomes in those with CRRT What are the outcomes in those with AKI? How often does it happen?

Neonatal AKI in VLBW Infants Prospective 18 month study at UAB Neonates with BW ≤ 1500 grams Categorical SCr based AKI definiton clinically-indicated measurements and remnant samples – 10 mcl of serum using Mass Spec No UOP criteria used Koralkar, Askenazi et al…Pediatric Research 2010

Neonatal AKI in VLBW Infants 18% incidence of AKI Koralkar et al…Pediatric Research 2010

Difference in Survival between infants with AKI and without AKI Death N = 26 Crude HR Adj** HR (95% CI) Any AKI No AKI 179 9 Ref 24 17 9.3 (4.1, 21.0) 2.3(0.9, 5.8) AKI Category AKI 1 7 3 6.8 (1.8, 25.0) 2.5 (0.6, 9.8) AKI 2 6.1 (1.6, 22.2) 1.6 (0.4, 6.1) AKI 3 10 11 12.4 (5.1, 30.1) 2.8 (1.0, 7.9) **controlled for Gestational age, Birth weight, High frequency ventilation Koralkar et al…Pediatric Research 2010

AKI in ELBW infants 472 ELBW Neonates at Case Western University AKI Definition SCr ≥ 1.5 mg/dl or UOP < 1 ml/kg/hr\ 12.5 % Incidence of AKI Viswanathan et al. Ped Nephrology 2012

AKI in ELBW infants 472 ELBW Neonates at Case Western University AKI Definition SCr ≥ 1.5 mg/dl or UOP < 1 ml/kg/hr 12.5 % Incidence of AKI Infants with AKI had increased mortality 33/46 (70%) vs. 10/46 (22%); p < 0.0001) oliguric patients higher mortality 31/38 (81%) vs. 2/8 (25%), p = 0.003. Viswanathan et al. Ped Nephrology 2012

Neonatal AKI in sick near-term/term infants admitted to level 2 and 3 NICU 58 Neonates admitted to Level 2 or 3 NICU No congenital anomalies of the kidney Birth weight > 2000 grams 5 minute Apgar ≤ 7 SCr criteria only 16% Incidence of AKI Askenazi et. al. Abstract at ASN 2011 - Philadelphia

Neonatal AKI in infants w/ perinatal asphyxia treated w/ hypothermia 96 consecutive infants at U. of Michigan AKIN 38% AKI Selewski , et al… abstract presented at CRRT 2012

Neonatal AKI in infants w/ perinatal asphyxia treated w/ hypothermia Variable AKI No AKI P Days in NICU 15.4 + 9.3 11.0 + 5.9 0.014 Days of Hospitalization 17.3 + 10.8 11.3 + 6.4 0.005 Days of Mechanical Ventilation 9.7 + 5.9 4.8 + 3.7 <0.001 Survival to ICU discharge * 31(86) 58(97) 0.099 Selewski , Askenazi et al… abstract presented at CRRT 2012

Neonatal AKI in infants with CDH on ECMO Infants with congenital diaphragmatic hernia on ECMO (retrospective study) Gadepalli SK, Selewski DT et. al. J Pediatr Surg. Apr 2011

Neonatal AKI in infants with CDH on ECMO Patients with stage RIFLE “failure” Increased time on ECMO Decreased ventilator free days Survival (p< 0.001) AKI = 27% No AKI = 80% Gadepalli SK, Selewski DT et. al. J Pediatr Surg. Apr 2011

Neonatal AKI after Cardio-pulmonary Bypass Surgery Retrospective chart review of 430 infants <90 days, (median age 7 days) with CHD. AKI was defined using a modified AKIN definition urine output criteria included Blinder JJ, et al.. J Thorac Cardiovasc Surg. 2011 Jul 26.

Neonatal AKI after Cardio-pulmonary Bypass Surgery Blinder JJ, et al.. J Thorac Cardiovasc Surg. July 2011

Neonatal AKI after Cardio-pulmonary Bypass Surgery AKI (all stages) - Longer ICU stay AKI stages 2 and 3 Increased mechanical ventilation Increased post-operative inotropic therapy. AKI was associated with higher mortality 27/225 (12%) vs. 6/205 (3%) P <0.001 Stage 2 OR for death = 5.1 (95% CI =1.7 – 15.2; p= 0.004) Stage 3 OR for death = 9.5 (95% CI = 2.9 – 30.7; p= .0002. Blinder JJ, et al.. J Thorac Cardiovasc Surg.

Outcomes Children < 10 kg receiving CRRT

Survival by Diagnosis N Survivors Am J Kid Dis, 18:833-837, 2003 36% 14 13 12 9 5 4 3 2 1 10 Congen Ht Dz Metabolic Multiorg Dysfxn Sepsis Liver failure Malignancy Congen Neph Synd Congen Diaph Hernia HUS Ht Failure Obstr Urop Renal Dyspl Other 36% 71% 15% 42% 22% 50% 100% 60% Percentages instead of numbers Totals: N=85; Survivors=32

Children < 10 kg in the ppCRRT Registry Survivors N = 36 Non-Survivors N = 48 p value Male Gender 21/36 (58%) 30/48 (63%) 0.82 Weight (kg) 5.0 5.2 0.71 Age (days) 255 335 0.68 Askenazi et.al. Journal of Pediatrics 2012 – in press

ppCRRT Data of Infants < 10 kg: Askenazi et.al. Journal of Pediatrics 2012 – in press

Smaller infants in ppCRRT have lower survival Askenazi et.al. Journal of Pediatrics 2012 – in press

Children < 10 kg in the ppCRRT Registry Primary Diagnosis N (%) Survivor Non- Survivors p-value Sepsis 25 / 84 (30%) 9/25 (36%) 16/25 (64%) 0.37 Cardiac Disease 16 /84 (19%) 6/16 (38%) 10/16 (62%) 0.59 Inborn Error of Metabolism 13/84 (15%) 8/13 (62%) 5/ 13 (38%) 0.15 hepatic 9/84 (11%) 0/9 (0%) 9 /9 (100%) < 0.01 Oncology* 6/84 (7%) 3/6 (50%) 0.73 Primary Pulmonary 5/ 84 (6%) 3/5 (60%) 2/5 (40%) 0.44 Renal ** 5/84 (6%) 4/5 (80%) 1/ 5 (20%) 0.09 Other *** 3/5 (75%) 0.19 * (3 neuroblastoma, 2 ALL, one hemophagocytic syndrome) ** (ARPKD, cortical necrosis, unknown \CKD, renal agenesis, congenital nephrotic *** (2 nephrotoxin , one congential diaphrmatic hernia, one omenn’s syndrome s/p bmt, one censored)

ppCRRT Data of Infants < 10 kg Survivor Non-Survivor P Mean Airway Pressure (at CRRT Conclusion) 11 20 <0.001 Pressor Dependency (throughout CRRT) 36% 69% <0.01 GI/Hepatic disease (present at CRRT start) 8% 31% 0.01 Urine output (ml/kg/hr) (at CRRT start) 2.4 1.0 0.02 Multiorgan system failure 68% 91% 0.04 PRISM score (at ICU admit) 16 21 <0.05 Askenazi et.al. Journal of Pediatrics 2012 – in press

Survival Differences by Fluid Overload in Infants < 10 kg enrolled in ppCRRT Askenazi et.al. Journal of Pediatrics 2012 – in press

Fluid overload is bad for neonates Variable Adjusted OR p-value PRISM II score at CRRT 1.1 (1.0 – 1.2) 0.02 Fluid Overload Groups       < 10 % vs. 10-20 % 0.9 (0.17 – 4.67) 0.25       < 10 % vs. > 20 % 4.8 (1.3-17.7) 0.01 UOP (ml/kg/hr) @ CRRT start 0.72 (0.53-0.97) 0.04 *66/84 observations used for analysis (40 death vs 26 Survival). variables used in the model include: PRISM 2 score, mean airway pressure (Paw) and urine output at CRRT, % fluid overload (categorically divided by 10% intervals), MODS and Inborn error of metabolism. Askenazi et.al. Journal of Pediatrics 2012 – in press

Small children are dialyzed differently! < 5kg N = 170 > 5kg N = 251 Anticoagulation <0.001 Citrate 76 (45%) 155 (62%) Heparin 94 (55%) 96 (38%) Prime Blood 164 (96.5%) 202 (80%) Saline 5 (3%) 29 (12%) Albumin 1 (0.5%) 20 (8%) Blood Flow * (ml/kg/min) 12 (7.9-15.6) 6.6 (4.8-8.8) Daily Effluent Volume* (ml/hr/1.73m2) 3328 (2325-4745) 2321 (1614-2895) Circuit LIfe 28 (11-67) 37 (16-67) 0.15 Askenazi et.al. Journal of Pediatrics 2012 – in press

Prescribing Pediatric CRRT

Which is better PD, HD or CRRT?

VS PD vs. HD vs. CRRT Each has advantages & disadvantages Choice is guided by Patient Characteristics Disease/Symptoms Hemodynamic stability Goals of therapy Fluid removal Electrolyte correction Both Availability, expertise and cost VS Pediatr Nephrol (2009) 24:37–48

Peritoneal dialysis Advantages Disadvantages No blood prime needed Low volume PD initiation soon after catheter insertion PD prescription 10 cc /kg dwell 10 minute fill / 40 minute / 10 minute drain Relatively low effort Disadvantages Risk of peritonitis Abdominal disease is contraindication Low clearances

Hemodialysis Advantages Disadvantages Highest efficiency High Effort and Cost High Acuity Accomplish Goals in 3 – 4 hours difficult Daily blood prime – implications on transplant

CRRT Advantages Disadvantages Slow and Steady Less Hemodynamic Instability ? More physiologic Disadvantages Cost Education of multiple bedside staff

Vascular Access for CRRT Put in the largest and shortest catheter when possible The IJ site is preferable (over femoral) when clinical situation allows A 7 or 8 F catheter may not fit in the femoral vein

Blood Prime for CRRT

Priming the Circuit for Pediatric CRRT Blood Small patient, large extracorporeal volume Albumin Hemodynamic instability Saline Common default approach Self Volume loaded renal failure patient

Pediatric CRRT Circuit Priming Smaller patients require blood priming to prevent hypotension/hemodilution Circuit volume > 10-15% patient blood volume Example 5 kg infant : Blood Volume = 400 cc (80/kg) Prismalex circuit – M60 extracorporeal volume ≈ 100 ml Therefore 25% extracorporeal volume

Added Risk for PRBC prime Packed RBCs HYPOCALCEMIC (I Ca++ = 0.2 Citrate HYPERKALEMIC (K+ = 5-12 meq/dl) LYSIS OF CELLS ACIDIC High HCT (70%) Protocols for initiation of CRRT use NaHCO3 and Calcium infusions around the time of initiation

Blood Primes Prime directly to the machine then hook up the patient Baby Buffer technique Give blood to baby and while you pull baby’s blood to prime circuit Dual Prisma Setup for restarts.

Blood Prime GO PRBC 10 ml / min 10 ml / min Brophy et al. AJKD 2001 NaHCO3 GO Calcium Gluconate Waste NS Bag Brophy et al. AJKD 2001 Blood Flow = 20 ml / min 49

Blood Prime PRBC NaHCO3 Waste NS Bag Brophy et al. AJKD 2001 50

Blood Prime GO Brophy et al. AJKD 2001 51

Neonatal Double CRRT Restart “Cross prime” from active circuit to new circuit Only good when current circuit functioning No new blood exposure Blood already equilibrated to patient Need several more hands

Neonatal Double CRRT Restart NS

Anticoagulation

Anticoagulation Regional Citrate Systemic Heparin Risk for Hypocalcemia Alkalosis Hypernatremia Newborns have decreased liver function High effluent rates Antibiotics Protein Vitamins carnatine Systemic Heparin Patient anticoagulated Risk of bleeding Risk for Heparin-Induced Thrombocytopenia HUGE issue in premies!

Choosing QB for Pediatric CRRT Clearance is Primarily Effluent Dependent on CRRT Remember that clearance rates need to be blood flow dependent when using citrate protocols…. The real determinant – the vascular access Try about 3-5 ml/kg / min 0-10 kg: 30-50ml/min 11-20kg: 80-100ml/min 21-50kg: 100-150ml/min >50kg: 150-180ml/min

5 kg with fluid overload and oliguria Prescription of RRT for pediatric patients Vascular access – Right IJ – place by surgeon Machinery - Prismaflex with M60 filter Priming the machine (ECV = 25% - BLOOD PRIME) Anticoagulation – citrate regional anticoagulation Blood flow rates – 40 ml/minute Clearance : modes, type and goals CVVHDF ( will need more than 2000 ml/1.73 m2) Net ultrafiltration goals Take an additional 10 ml per hour

Future of Neonatal AKI

How do we improve renal support in neonates? Timing of RRT? Type of RRT? Blood prime protocols Current technology not designed for neonates Smaller extracorporeal volumes Higher precision Dedicated to neonates

Summary Neonatal AKI is common and is associated with poor outcomes Choice of PD vs. HD vs. CRRT are patient and goal specific CRRT can be an effective therapy for even the smallest patients The possibility of a dedicated device for neonates may open further options

Thanks!